Wound healing is a carefully orchestrated series of events with overlapping temporal and spatial relationships, and includes phases of inflammation, proliferation, and remodeling (Guo et al., Journal Dent Res, 89:219-229 (2010); Shih et al., Wound Repair Regeneration, 18:139-153 (2010)). Some of the processes in wound repair that have been implicated as responsible factors include abnormalities in inflammation, migration, angiogenesis, neovascularization, cell proliferation, formation of granulation tissue and collagen, and re-epithelialization (Usui et al., Journal of Histochem Cytochem, 56:687-696 (2008); Mustoe et al, American Journal of Surgery, 187:655-705 (2004); Brem et al., Arch Surg, 135:627-634 (2000)).
In Type 1 diabetes, wounds often fail to progress through the normal stages of healing (Boulton et al., Lancet, 366:1719-1724 (2005); Usui et al., Journal of Histochem Cytochem, 56:687-696 (2008)). Impaired wound healing is a major complication of diabetes that can result in the formation of chronic debilitating ulcers (Guo et al., Journal Dent Res, 89:219-229 (2010); Boulton et al., Lancet, 366:1719-1724 (2005); O'Loughlin et al., International Journal of Lower Extremity Wounds, 9:90-102 (2010)). Diabetes is the leading cause of amputations (Boulton et al., Lancet, 366:1719-1724 (2005); O'Loughlin et al., International Journal of Lower Extremity Wounds, 9:90-102 (2010)), accounting for over 50% of patients having lower extremity amputations annually. With the number of diabetic patients estimated to reach 300 million world-wide by the year 2030, the burden of diabetic wounds and their complications is expected to rise simultaneously (Boulton et al., Lancet, 366:1719-1724 (2005)). Although continuing medical care and patient self-management reduce the risk of long-term complications, and despite the availability of numerous dressing products, there is no fully effective prevention or treatment of these complications.
Initially studied for their role as neurotransmitters (Akil et al., Ann Rev Neuroscience, 7:223-255 (1984)), endogenous opioids have been shown to be present in neural and non-neural tissues, and to mediate a number of functions other than neuromodulation including cell proliferation, angiogenesis, tissue organization, cell migration, and immunity (Zagon et al., Journal of Invest Dermatology, 106:490-497 (1996); Zagon et al., Diabetes, 51:3055-3062 (2002); Zagon et al., Journal of Vascular Surgery, 37:636-643 (2003); Blebea et al., Journal of Vascular Surgery, 32:364-373 (2000); Zagon et al., Immunobiology, 216:173-183 (2011); Zagon et al., Immunobiology, 216:579-590 (2011); Wilson et al., Cell Prolif, 33:63-73 (2000)). The endogenous opioids include dynorphins, enkephalins, endorphins, endomorphins and nociceptin. Classical opioid receptors are the μ, δ, and κ receptors; non-classical opioid receptors include the nociceptin receptor and the opioid growth factor receptor (OGFr), also referred to as the ζ (zeta) receptor (Corbett et al. Br. J. Pharmacol. 147 Suppl 1: S153-62 (2006)). The endogenous ligand for OGFr is [Met5]-enkephalin, also called opioid growth factor (OGF).
The relationship of native opioids to diabetes has received some attention. Studies concerned with circulating opioid levels in diabetes have shown that patients with type 1 diabetes (T1D) have high plasma [Met5]-enkephalin levels (Fallucca et al., Metabolism, 45:1065-1068 (1996); Negri et al., Metabolism, 41:460-461 (1992); Kolta et al., Neuropeptides, 21:55-63 (1992)). Elevated levels of [Met5]-enkephalin also have been reported in plasma of genetically obese diabetic (db/db) mice (Timmers et al., Diabetes, 35:1143-1151 (1986); Greenberg et al. Endocrinology, 116:328-331 (1985)).
A series of studies using systemic and topical applications of the opioid antagonist naltrexone (NTX) in rats with T1D reported delays in re-epithelialization following removal of ocular surface epithelium that were reversed by NTX and related to an increase in DNA synthesis (Zagon et al., Diabetes, 51:3055-3062 (2002); Klocek et al., Journal of Ocular Pharmacology and Therapeutics, 23:89-102 (2007)). These data suggest that dysfunctional ocular wound repair in T1D was due to an increase in opioid peptide-opioid receptor interactions that were disrupted by NTX. OGF is known to suppress re-epithelialization in the human cornea (Zagon et al., Investigative Ophthalmology & Visual Science, 41:73-81 (2000)) and rat tail skin (Wilson et al., Cell Prolif, 33:63-73 (2000)).
Endogenous opioids, and classical and non-classical opioid receptors, are present in epithelial tissues (Cheng et al., Clin Lab Invest, 158:713-720 (2008); Wintzen et al., Exp Dermatol, 10:305-311 (2001); Tominaga Journal of Invest Dermatol, 127:2228-2235 (2007); Bigliardi-Qi et al., Differentiation, 74:174-185 (2006); Nissen et al., Experimental Dermatology, 6:222-229 (1997); Wenk et al., Journal of Comp Neurol, 408:567-579 (1999); Salemi et al., Biochem Biophys Res Commun, 338:1012-1017 (2005); Zagon et al., Cell Tissue Research, 246:561-565 (1986); Bigliardi et al., Journal of Invest Dermatol, 111:297-301 (1998); Kauser et al., Journal of Invest Dermatol, 120:1073-1080 (2003)). OGF is known to regulate DNA synthesis and cellular renewal of the stratum corneum, (Wintzen et al., Exp Dermatol, 10:305-311 (2001)) whereas deletion of the δ opioid receptor in mice alters skin differentiation and delays wound healing (Bigliardi-Qi et al., Differentiation, 74:174-185 (2006)).
There is an urgent need to understand the pathophysiology underlying wound healing in diabetes and other situations in which wound healing is delayed, and to translate this knowledge into treatment modalities in order to prevent or at least attenuate acute and chronic wound healing complications (Usui et al., Journal of Histochem Cytochem, 56:687-696 (2008)).